Zykadia Approved for Metastatic, ALK-Positive Lung Cancer
The FDA approved ceritinib (Zykadia; Novartis) for the treatment of patients with metastatic, anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC) on April 29, 2014. Ceritinib is an ALK tyrosine kinase inhibitor (TKI) that blocks proteins that promote cancer-cell growth. The drug is approved for the treatment of patients with late-stage NSCLC who were previously treated with crizotinib, the first and only other ALK TKI approved by the FDA for this indication.
The FDA had granted ceritinib a breakthrough therapy and an orphan drug designation, as well as a priority review based on preliminary clinical results provided by the manufacturer that demonstrated the drug’s safety and efficacy, indicating that ceritinib offered a substantial improvement over currently available therapies for this specific indication.
The FDA approved ceritinib under its accelerated approval process 4 months ahead of the scheduled final review date to expedite access to this drug for a patient population facing a life-threatening condition and very few available treatment options.
“Today’s approval illustrates how a greater understanding of the underlying molecular pathways of a disease can lead to the development of specific therapies aimed at these pathways,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
The safety and efficacy of ceritinib were established in a clinical trial with 163 patients with metastatic, ALK-positive NSCLC. In the trial, all patients received ceritinib therapy; approximately 50% of the patients had their tumor shrink with this therapy, and this lasted an average of approximately 7 months.
Reported side effects were mainly gastrointestinal, such as diarrhea, nausea, vomiting, and abdominal pain. Laboratory abnormalities included increased liver enzymes and pancreatic enzymes, as well as increased glucose levels.
FDA Approves Ofatumumab for Patients with Chronic Lymphocytic Leukemia
On April 17, 2014, the FDA approved ofatumumab (Arzerra Injection, GlaxoSmithKline) in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL), for whom fludarabine-based therapy is considered inappropriate.
The approval was based on the results of a multicenter, randomized, open-label trial comparing ofatumumab in combination with chlorambucil with chlorambucil alone. The 447 patients included in the study were deemed ineligible for fludarabine-based therapy because of advanced age or comorbidities. Overall, 72% of patients had ≥2 comorbidities, and 48% had a creatinine clearance of <70 mL/min.
Infusion of intravenous (IV) ofatumumab was administered as 300 mg in cycle 1 on day 1, followed by 1000 mg on day 8 (first arm), or 1000 mg administered on day 1 of all subsequent 28-day cycles (second arm). In both arms, chlorambucil was administered at a dose of 10 mg/m2 orally on days 1 to 7 every 28 days. Before each infusion of IV ofatumumab, patients received premedication with acetaminophen, an antihistamine, and a glucocorticoid.
The primary end point of the trial was progression-
free survival (PFS) as assessed by a blinded independent review committee. The median PFS was 22.4 months (95% confidence interval [CI], 19-25.2) in patients receiving ofatumumab plus chlorambucil compared with 13.1 months (95% CI, 10.6-13.8) in patients receiving chlorambucil alone (hazard ratio, 0.57; 95% CI, 0.45-0.72; P <.001).
The most common adverse reactions (≥5%) reported with ofatumumab plus chlorambucil were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain. Overall, 67% of the patients who received ofatumumab had ≥1 symptoms of infusion reaction. In addition, 10% of patients had a grade ≥3 infusion reaction.
The recommended regimen for ofatumumab in patients with previously untreated CLL is 300 mg on day 1, followed by 1000 mg on day 8 (cycle 1), followed by 1000 mg on day 1 of the subsequent 28-day cycles, for a minimum of 3 cycles and a maximum of 12 cycles.
Ramucirumab First FDA-Approved Drug for Advanced Stomach Cancer after Chemotherapy
On April 21, 2014, the FDA approved ramucirumab (Cyramza; Eli Lilly) for the treatment of patients with advanced stomach cancer or gastroesophageal junction adenocarcinoma, which mostly affects older adults. Ramucirumab is an angiogenesis inhibitor that blocks the blood supply to tumors and is intended to be used in patients with unresectable cancer or with metastatic stomach cancer after receiving chemotherapy with a fluoropyrimidine- or a platinum-containing agent. This is the first FDA-approved therapy for patients with stomach cancer who have already received chemotherapy.
“Although the rates of stomach cancer in the United States have decreased over the past 40 years, patients require new treatment options, particularly when they no longer respond to other therapies,” said Dr Pazdur. “Cyramza is a new treatment option that has demonstrated an ability to extend patients’ lives and slow tumor growth.”
Ramucirumab was approved under the FDA’s priority review program, and was also granted an orphan drug status, because it is intended to treat rare conditions.
The safety and efficacy of ramucirumab were demonstrated in a clinical trial of 355 patients with unresectable or metastatic stomach or gastroesophageal junction cancer. Patients were randomized to ramucirumab (66%) or to placebo (34%). The main end point was overall survival (OS). The median OS was 5.2 months with ramuciru-mab compared with 3.8 months with placebo (P <.001). Ramucirumab also improved PFS compared with placebo.
Results from a second clinical trial that evaluated the efficacy of ramucirumab plus paclitaxel versus paclitaxel alone also showed an OS improvement with the addition of ramucirumab.
Common adverse events reported with ramucirumab in clinical trials include diarrhea and high blood pressure. The recommended dose of ramucirumab is 8 mg/kg every 2 weeks administered as an IV infusion over 60 minutes until disease progression or unacceptable toxicity.
Palonosetron Receives New Indication for the Prevention of CINV in Pediatric Patients
On May 28, 2014, the FDA approved a new indication for palonosetron HCl (Aloxi; Eisai) injection for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) associated with initial or repeated courses of emetogenic chemotherapy in children aged 1 month to <17 years. This is the first FDA approval of a therapy for the prevention of acute CINV in patients aged 1 month to 6 months. The age of peak cancer incidence among children occurs within the first year of life, so this approval offers an important option to children, and especially infants, undergoing chemotherapy.
The FDA approval was based on 1 randomized, double-blind, noninferiority pivotal trial comparing palonosetron with ondansetron in pediatric patients. The primary end point was complete response (CR), defined as no vomiting, retching, or antiemesis rescue medication required within the first 24 hours after chemotherapy. CR was achieved in 59.4% of the patients using palonosetron compared with 58.6% of patients receiving ondansetron.
The trial also showed that pediatric patients required a higher dose of palonosetron based on weight than that required by adults; however, the safety profile of the drug in pediatric patients was consistent with its safety profile in adults.
Adverse events were comparable across both arms; the most frequently reported adverse event with palonosetron was headache.
Palonosetron is already approved for the prevention of CINV in adults aged ≥17 years.
Zykadia Approved for Metastatic, ALK-Positive Lung Cancer